Nature agingJul 21, 2026

Aging cells gather CTCF protein at nuclear speckles to control alternative RNA splicing

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 23, 2026

Abstract

Cells reorganize a protein called CTCF into clusters during senescence, which may influence alternative splicing and the timing of senescence onset.

Senescence leads to the clustering of CTCF into structures known as senescence-induced clusters (SICCs).
The repurposing of SRRM2 and BANF1 is involved in the formation of these CTCF clusters.
This clustering contributes to changes in genome architecture that affect splicing programs.
Disruption of SICCs can reverse alternative splicing patterns and delay the onset of senescence.
These findings suggest a mechanism where nuclear changes direct gene expression to influence cell fate.

Simplified

Senescence, the endpoint of normal cells' replicative lifespan, is accompanied by a complex sequence of molecular events. One such event is the dramatic reorganization of CTCF into senescence-induced clusters (SICCs). However, the molecular determinants, genomic consequences and functional purpose of SICCs remain unknown. Here we combine three-dimensional genomics, super-resolution imaging, DNA tracing and functional assays with modeling to dissect SICC emergence. We find that, on senescence entry, cells repurpose SRRM2-a key component of nuclear speckles-and BANF1-a 'molecular glue' for chromosomes-to cluster CTCF and rewire genome architecture. This CTCF-centric reorganization in reference to nuclear speckles helps instruct the senescence splicing program, because disruption of SICCs almost fully reverts alternative splicing patterns and delays senescence onset. We therefore uncover a paradigm whereby human cells translate changes in nuclear biochemistry into architectural changes directing splicing choices to commit to the fate of senescence.